Derivatives of dimethylcurcumin

ABSTRACT

The invention relates to compounds of Formula I or Ia as disclosed herein: 
                         
or pharmaceutically acceptable salts thereof or tautomers thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119(e) to U.S.Provisional Application No. 61/314,842, filed Mar. 17, 2010, which isincorporated by reference herein in its entirety.

BACKGROUND OF THE INVENTION

Many current medicines suffer from poor absorption, distribution,metabolism and/or excretion (ADME) properties that prevent their wideruse. Poor ADME properties are also a major reason for the failure ofdrug candidates in clinical trials. While formulation technologies andprodrug strategies can be employed in some cases to improve certain ADMEproperties, these approaches often fail to address the underlying ADMEproblems that exist for many drugs and drug candidates. One such problemis rapid metabolism that causes a number of drugs, which otherwise wouldbe highly effective in treating a disease, to be cleared too rapidlyfrom the body. A possible solution to rapid drug clearance is frequentor high dosing to attain a sufficiently high plasma level of drug. This,however, introduces a number of potential treatment problems such aspoor patient compliance with the dosing regimen, side effects thatbecome more acute with higher doses, and increased cost of treatment.

In some select cases, a metabolic inhibitor will be co-administered witha drug that is cleared too rapidly. Such is the case with the proteaseinhibitor class of drugs that are used to treat HIV infection. The FDArecommends that these drugs be co-dosed with ritonavir, an inhibitor ofcytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsiblefor their metabolism (see Kempf, D. J. et al., Antimicrobial agents andchemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverseeffects and adds to the pill burden for HIV patients who must alreadytake a combination of different drugs. Similarly, the CYP2D6 inhibitorquinidine has been added to dextromethorphan for the purpose of reducingrapid CYP2D6 metabolism of dextromethorphan in a treatment ofpseudobulbar affect. Quinidine, however, has unwanted side effects thatgreatly limit its use in potential combination therapy (see Wang, L etal., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67;and FDA label for quinidine at www.accessdata.fda.gov).

In general, combining drugs with cytochrome P450 inhibitors is not asatisfactory strategy for decreasing drug clearance. The inhibition of aCYP enzyme's activity can affect the metabolism and clearance of otherdrugs metabolized by that same enzyme. CYP inhibition can cause otherdrugs to accumulate in the body to toxic levels.

A potentially attractive strategy for improving a drug's metabolicproperties is deuterium modification. In this approach, one attempts toslow the CYP-mediated metabolism of a drug by replacing one or morehydrogen atoms with deuterium atoms. Deuterium is a safe, stable,non-radioactive isotope of hydrogen. Compared to hydrogen, deuteriumforms stronger bonds with carbon. In select cases, the increased bondstrength imparted by deuterium can positively impact the ADME propertiesof a drug, creating the potential for improved drug efficacy, safety,and/or tolerability. At the same time, because the size and shape ofdeuterium are essentially identical to those of hydrogen, replacement ofhydrogen by deuterium would not be expected to affect the biochemicalpotency and selectivity of the drug as compared to the original chemicalentity that contains only hydrogen.

Over the past 35 years, the effects of deuterium substitution on therate of metabolism have been reported for a very small percentage ofapproved drugs (see, e.g., Blake, M I et al, J Pharm Sci, 1975,64:367-91; Foster, A B, Adv Drug Res 1985, 14:1-40 (“Foster”); Kushner,D J et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, M B et al, CurrOpin Drug Discov Devel, 2006, 9:101-09 (“Fisher”)). The results havebeen variable and unpredictable. For some compounds deuteration causeddecreased metabolic clearance in vivo. For others, there was no changein metabolism. Still others demonstrated increased metabolic clearance.The variability in deuterium effects has also led experts to question ordismiss deuterium modification as a viable drug design strategy forinhibiting adverse metabolism (see Foster at p. 35 and Fisher at p.101).

The effects of deuterium modification on a drug's metabolic propertiesare not predictable even when deuterium atoms are incorporated at knownsites of metabolism. Only by actually preparing and testing a deuterateddrug can one determine if and how the rate of metabolism will differfrom that of its non-deuterated counterpart. See, for example, Fukuto etal. (J. Med. Chem. 1991, 34, 2871-76). Many drugs have multiple siteswhere metabolism is possible. The site(s) where deuterium substitutionis required and the extent of deuteration necessary to see an effect onmetabolism, if any, will be different for each drug.

This invention relates to novel derivatives of curcumin anddimethylcurcumin and pharmaceutically acceptable salts thereof. Thisinvention also provides compositions comprising a compound of thisinvention and the use of such compositions in methods of treatingdiseases and conditions that are beneficially treated by administeringcurcumin or dimethylcurcumin.

Curcuminoids such as dimethylcurcumin are capable of acting as androgenreceptor antagonists. Such compounds may be useful for the treatment ofandrogen-related afflictions including baldness, hirsutism, behavioraldisorders, acne, alopecia, skin lesions, Kennedy's disease orspinobulbar muscular atrophy and spermatogenesis where inhibition ofspermatogenesis is desired. Additionally, the compounds may be usefulfor treatment of psoriasis, Alzheimer's disease, mild cognitiveimpairment, asthma, type 2 diabetes, optic neuropathy, rheumatoidarthritis, osteoarthritis, major depressive disorder, kidney allografts,oral lichen planus, irritable bowel syndrome (IBS), ulcerative colitis,Crohn's disease, chemoradiation side effects including but not limitedto radiation induced dermatitis and chemotherapy induced mucositis andcancer including, but not limited to, multiple myeloma, pancreaticcancer, myleodysplastic syndromes, colon cancer, colorectal cancer, skincancer, small cell lung cancer, testicular cancer, lymphoma, leukemia,esophageal cancer, stomach cancer, breast cancer, endometrial cancer,ovarian cancer, central nervous system cancer, liver cancer, prostatecancer, familial adenomatous polyposis (FAP), uterine cervicaldysplasia, cutaneous T-cell lymphoma, head and neck cancer andosteosarcoma.

Dimethylcurcumin is currently undergoing clinical trial evaluation foruse in topical treatment of acne and alopecia. Preclinical studies arealso underway for the treatment of skin lesions and Kennedy's disease orspinobulbar muscular atrophy. Curcumin is currently undergoing clinicaltrial evaluation for use in treatment of asthma, type 2 diabetes,Alzheimer's disease, mild cognitive impairment, optic neuropathy,rheumatoid arthritis, osteoarthritis, major depressive disorder, kidneyallografts, psoriasis, oral lichen planus, multiple myeloma,myelodysplastic syndrome, colorectal cancer, familial adenomatouspolyposis (FAP), uterine cervical dysplasia, cutaneous T-cell lymphoma,head and neck cancer, pancreatic cancer, osteosarcoma, irritable bowelsyndrome (IBS), ulcerative colitis, Crohn's disease, chemoradiation sideeffects including but not limited to radiation induced dermatitis andchemotherapy induced mucositis.

Despite the beneficial activities of dimethylcurcumin, there is acontinuing need for compositions or derivatives thereof that provide thebeneficial effects of dimethylcurcumin, but reduce or avoid the adverseside effects.

DEFINITIONS

The term “treat” means decrease, suppress, attenuate, diminish, arrest,or stabilize the development or progression of a disease (e.g., adisease or disorder delineated herein), lessen the severity of thedisease or improve the symptoms associated with the disease.

“Disease” means any condition or disorder that damages or interfereswith the normal function of a cell, tissue, or organ.

The term “alkyl” refers to a monovalent saturated hydrocarbon group. AC₁-C₆ alkyl is an alkyl having from 1 to 6 carbon atoms. An alkyl may belinear or branched. Examples of alkyl groups include methyl; ethyl;propyl, including n-propyl and isopropyl; butyl, including n-butyl,isobutyl, sec-butyl, and t-butyl; pentyl, including, for example,n-pentyl, isopentyl, and neopentyl; and hexyl, including, for example,n-hexyl and 2-methylpentyl.

The term “alkenyl” refers to a monovalent saturated hydrocarbon grouphaving one or more double bonds. A C₂-C₆ alkenyl is an alkenyl havingfrom 2 to 6 carbon atoms. An alkenyl may be linear or branched. Examplesof alkenyl groups include CH₂═CH—; CH₃—CH═CH—; —CH₂═CH—CH₂—;(CH₃)₂C═CH—; CH₂═C(CH₃)—CH₂—; and (CH₃)₂CH—CH═CH—.

It will be recognized that some variation of natural isotopic abundanceoccurs in a synthesized compound depending upon the origin of chemicalmaterials used in the synthesis. Thus, a preparation of dimethylcurcuminwill inherently contain small amounts of deuterated isotopologues. Theconcentration of naturally abundant stable hydrogen and carbon isotopes,notwithstanding this variation, is small and immaterial as compared tothe degree of stable isotopic substitution of compounds of thisinvention. See, for instance, Wada, E et al., Seikagaku, 1994, 66:15;Gannes, L Z et al., Comp Biochem Physiol Mol Integr Physiol, 1998,119:725.

In the compounds of this invention any atom not specifically designatedas a particular isotope is meant to represent any stable isotope of thatatom. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition. Also unlessotherwise stated, when a position is designated specifically as “D” or“deuterium”, the position is understood to have deuterium at anabundance that is at least 3340 times greater than the natural abundanceof deuterium, which is 0.015% (i.e., at least 50.1% incorporation ofdeuterium).

The term “isotopic enrichment factor” as used herein means the ratiobetween the isotopic abundance and the natural abundance of a specifiedisotope.

In other embodiments, a compound of this invention has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium), at least 5500 (82.5%deuterium incorporation), at least 6000 (90% deuterium incorporation),at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97%deuterium incorporation), at least 6600 (99% deuterium incorporation),or at least 6633.3 (99.5% deuterium incorporation).

The term “isotopologue” refers to a species in which the chemicalstructure differs from a specific compound of this invention only in theisotopic composition thereof.

The term “compound,” when referring to a compound of this invention,refers to a collection of molecules having an identical chemicalstructure, except that there may be isotopic variation among theconstituent atoms of the molecules. Thus, it will be clear to those ofskill in the art that a compound represented by a particular chemicalstructure containing indicated deuterium atoms, will also contain lesseramounts of isotopologues having hydrogen atoms at one or more of thedesignated deuterium positions in that structure. The relative amount ofsuch isotopologues in a compound of this invention will depend upon anumber of factors including the isotopic purity of deuterated reagentsused to make the compound and the efficiency of incorporation ofdeuterium in the various synthesis steps used to prepare the compound.However, as set forth above the relative amount of such isotopologues intoto will be less than 49.9% of the compound. In other embodiments, therelative amount of such isotopologues in toto will be less than 47.5%,less than 40%, less than 32.5%, less than 25%, less than 17.5%, lessthan 10%, less than 5%, less than 3%, less than 1%, or less than 0.5° Aof the compound.

The invention also provides salts of the compounds of the invention.

A salt of a compound of this invention is formed between an acid and abasic group of the compound, such as an amino functional group, or abase and an acidic group of the compound, such as a carboxyl functionalgroup. According to another embodiment, the compound is apharmaceutically acceptable acid addition salt.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent that is, within the scope of sound medical judgment, suitablefor use in contact with the tissues of humans and other mammals withoutundue toxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. A “pharmaceuticallyacceptable salt” means any non-toxic salt that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention. A “pharmaceutically acceptable counterion”is an ionic portion of a salt that is not toxic when released from thesalt upon administration to a recipient.

Acids commonly employed to form pharmaceutically acceptable saltsinclude inorganic acids such as hydrogen bisulfide, hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, aswell as organic acids such as para-toluenesulfonic acid, salicylic acid,tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylicacid, fumaric acid, gluconic acid, glucuronic acid, formic acid,glutamic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonicacid, carbonic acid, succinic acid, citric acid, benzoic acid and aceticacid, as well as related inorganic and organic acids. Suchpharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephthalate, sulfonate, xylene sulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, O-hydroxybutyrate,glycolate, maleate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and othersalts. In one embodiment, pharmaceutically acceptable acid additionsalts include those formed with mineral acids such as hydrochloric acidand hydrobromic acid, and especially those formed with organic acidssuch as maleic acid.

The compounds of the present invention (e.g., compounds of Formula I),may contain an asymmetric carbon atom, for example, as the result ofdeuterium substitution or otherwise. As such, compounds of thisinvention can exist as either individual enantiomers, or mixtures of thetwo enantiomers. Accordingly, a compound of the present invention mayexist as either a racemic mixture or a scalemic mixture, or asindividual respective stereoisomers that are substantially free fromanother possible stereoisomer. The term “substantially free of otherstereoisomers” as used herein means less than 25% of otherstereoisomers, preferably less than 10% of other stereoisomers, morepreferably less than 5% of other stereoisomers and most preferably lessthan 2% of other stereoisomers are present. Methods of obtaining orsynthesizing an individual enantiomer for a given compound are known inthe art and may be applied as practicable to final compounds or tostarting material or intermediates.

Unless otherwise indicated, when a disclosed compound is named ordepicted by a structure without specifying the stereochemistry and hasone or more chiral centers, it is understood to represent all possiblestereoisomers of the compound.

The term “stable compounds,” as used herein, refers to compounds whichpossess stability sufficient to allow for their manufacture and whichmaintain the integrity of the compound for a sufficient period of timeto be useful for the purposes detailed herein (e.g., formulation intotherapeutic products, intermediates for use in production of therapeuticcompounds, isolatable or storable intermediate compounds, treating adisease or condition responsive to therapeutic agents).

“D” and “d” both refer to deuterium. “Stereoisomer” refers to bothenantiomers and diastereomers. “Tert” and “t-” each refer to tertiary.“US” refers to the United States of America.

The term “substituted with deuterium” means that one or more hydrogenatoms in the indicated moiety are substituted with a deuterium atom.

Therapeutic Compounds

The present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof or a tautomer thereof,wherein:

R¹, R², R³ and R⁴ are each independently selected from the groupconsisting of —OH, —O(C₁-C₆ alkyl), —NO₂, —NH₂, —NH(C₁-C₆ alkyl) and—N(C₁-C₆ alkyl)₂, wherein each C₁-C₆ alkyl is optionally andindependently substituted with one or more deuterium;

R⁵ and R⁶ are each independently hydrogen, deuterium, halo, or —NO₂;

R⁷ is hydrogen, deuterium, or —R¹³;

R¹³ is (C₂-C₆) alkenyl optionally substituted with one or more deuteriumand substituted with —C(O)R¹²;

R¹² is —OCH₃, —OCH₂CH₃, —NH(CH₂CH₃), —CN, or —CH₂OH, wherein each of—OCH₃, —OCH₂CH₃, —NH(CH₂CH₃), and —CH₂OH is optionally substituted withone or more deuterium;

R⁸ and R¹¹ are each independently hydrogen or deuterium;

R⁹ and R¹⁰ are each independently hydrogen or deuterium;

X¹ and X² are each independently N, CH, CD, C(OCH₃), C(OCD₃) or C(NO₂);

provided that at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹¹, R⁹,R¹⁰, X¹ and X² comprises deuterium;

and provided that the compound of Formula I is not

In one embodiment of the invention, R¹, R², R³, and R⁴ are independentlyselected from —OH, —OCH₃, and —OCD₃.

In one embodiment, R⁵ and R⁶ are each hydrogen or each deuterium.

In one embodiment, R⁷ is hydrogen or deuterium.

In one embodiment, X¹ is CH or CD.

In one embodiment, X² is CH or CD.

In one embodiment, R⁷ is R¹³, wherein R¹³ is (C₂-C₆) alkenyl optionallysubstituted with one or more deuterium and with —C(O)R¹², and R¹² is—OCD₃, —OCD₂CD₃, —N(H)CD₂CD₃, or —CD₂OH.

Examples of compounds of Formula I wherein X¹═X²═CH and R⁵═R⁶═H includethe following compounds or pharmaceutically acceptable salts thereof ortautomers thereof, wherein any atom not designated as deuterium ispresent at its natural isotopic abundance:

TABLE 1 Examples of Compounds of Formula I wherein X¹═X²═CH and R⁵═R⁶═HCom- pound R¹ R² R³ R⁴ R⁷ R⁸ R⁹ R¹⁰ R¹¹ 100 OCD₃ OCD₃ OH OCD₃ D D D D D101 OCD₃ OCD₃ OH OCD₃ H D D D D 102 OCD₃ OCD₃ OH OCD₃ H H D D D 103 OCD₃OCD₃ OH OCD₃ H D D D H 104 OCD₃ OCD₃ OH OCD₃ H H D D H 105 OCD₃ OCD₃ OHOCD₃ H H H H H 106 OCD₃ OCD₃ OH OCD₃ H D H H D 107 OCD₃ OCD₃ OH OCD₃ H DH H H 108 OCD₃ OCD₃ OH OCD₃ H H H H D 109 OCH₃ OCD₃ OH OCD₃ D D D D D110 OCH₃ OCD₃ OH OCD₃ H D D D D 111 OCH₃ OCD₃ OH OCD₃ H H D D D 112 OCH₃OCD₃ OH OCD₃ H D D D H 113 OCH₃ OCD₃ OH OCD₃ H H D D H 114 OCH₃ OCD₃ OHOCD₃ H H H H H 115 OCH₃ OCD₃ OH OCD₃ H D H H D 116 OCH₃ OCD₃ OH OCD₃ H DH H H 117 OCH₃ OCD₃ OH OCD₃ H H H H D 118 OCD₃ OCH₃ OH OCH₃ D D D D D119 OCD₃ OCH₃ OH OCH₃ H D D D D 120 OCD₃ OCH₃ OH OCH₃ H H D D D 121 OCD₃OCH₃ OH OCH₃ H D D D H 122 OCD₃ OCH₃ OH OCH₃ H H D D H 123 OCD₃ OCH₃ OHOCH₃ H H H H H 124 OCD₃ OCH₃ OH OCH₃ H D H H D 125 OCD₃ OCH₃ OH OCH₃ H DH H H 126 OCD₃ OCH₃ OH OCH₃ H H H H D 127 OCH₃ OCH₃ OH OCH₃ D D D D D128 OCH₃ OCH₃ OH OCH₃ H D D D D 129 OCH₃ OCH₃ OH OCH₃ H H D D D 130 OCH₃OCH₃ OH OCH₃ H D D D H 131 OCH₃ OCH₃ OH OCH₃ H H D D H 132 OCH₃ OCH₃ OHOCH₃ H D H H D 133 OCH₃ OCH₃ OH OCH₃ H D H H H 134 OCH₃ OCH₃ OH OCH₃ H HH H D

In one embodiment, the compound is compound 100, 101, 102, 103, 104,105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118,119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 133 or134 in Table 1, or a pharmaceutically acceptable salt thereof or atautomer thereof.

In one embodiment, the compound of Formula I is a compound of FormulaIa:

or a pharmaceutically acceptable salt thereof or a tautomer thereof,wherein:

R¹ and R² are the same and are selected from the group consisting of—OH, —O(C₁-C₆ alkyl), —NO₂, —NH₂, —NH(C₁-C₆ alkyl) and —N(C₁-C₆ alkyl)₂,wherein each C₁-C₆ alkyl is optionally and independently substitutedwith one or more deuterium;

R³ and R⁴ are the same and are selected from the group consisting of—OH, —O(C₁-C₆ alkyl), —NO₂, —NH₂, —NH(C₁-C₆ alkyl) and —N(C₁-C₆ alkyl)₂,wherein each C₁-C₆ alkyl is optionally and independently substitutedwith one or more deuterium;

R⁵ and R⁶ are the same and are selected from the group consisting ofhydrogen and deuterium;

R⁷ is selected from hydrogen and deuterium;

R⁹ and R¹⁰ are the same and are selected from hydrogen and deuterium;

R⁸ and R¹¹ are the same and are selected from hydrogen and deuterium;

R¹⁴ and R¹⁵ are the same and are selected from hydrogen and deuterium;

provided that at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹¹, R⁹,R¹⁰, R¹⁴ and R¹⁵ comprises deuterium;

and provided that the compound of Formula Ia is not

In one embodiment of the compound of Formula Ia, R⁷, R⁹ and R¹⁰ are thesame and are selected from hydrogen and deuterium.

In another embodiment of the compound of Formula Ia, R¹ and R² are thesame and are selected from —OH, R¹ and R² are both —OCH₃ and —OCD₃; andR³ and R⁴ are the same and are selected from —OH, —OCH₃ and —OCD₃.Alternatively, —OCH₃ and —OCD₃; and R³ and R⁴ are both —OH.

In another set of embodiments of Formula I or Ia, any atom notdesignated as deuterium in any of the embodiments set forth above ispresent at its natural isotopic abundance.

Examples of compounds of Formula Ia, wherein R⁵═R⁶═H, and R¹⁴═R¹⁵═H, arethe following compounds or pharmaceutically acceptable salts thereof ortautomers thereof, wherein any atom not designated as deuterium ispresent at its natural isotopic abundance:

TABLE 2 Example of Compounds of Formula Ia Compound R¹═R² R³═R⁴ R⁷R⁸═R¹¹ R⁹═R¹⁰ 200 OCD₃ OCD₃ D D D 201 OCD₃ OCH₃ D D D 202 OCH₃ OCD₃ D DD 203 OCH₃ OCH₃ D D D 204 OCD₃ OCD₃ D H D 205 OCD₃ OCD₃ H D H 206 OCD₃OCH₃ D H D 207 OCD₃ OCH₃ H D H 208 OCH₃ OCD₃ D H D 209 OCH₃ OCD₃ H D H210 OCH₃ OCH₃ D H D 211 OCH₃ OCH₃ H D H 212 OCD₃ OCD₃ H H H 213 OCD₃OCH₃ H H H 214 OCH₃ OCD₃ H H H 215 OCD₃ OCD₃ H D D 216 OCD₃ OCH₃ H D D217 OCH₃ OCD₃ H D D 218 OCH₃ OCH₃ H D D 219 OCD₃ OCD₃ H H D 220 OCD₃OCH₃ H H D 221 OCH₃ OCD₃ H H D 222 OCH₃ OCH₃ H H D

In one embodiment, the compound is compound 200, 201, 202, 203, 204,205, 206, 207, 208, 209, 210, 212, 213, 214, 215, 216, 217, 218, 219,220, 221 or 222 in Table 2, or a pharmaceutically acceptable saltthereof or a tautomer thereof.

Additional examples of compounds of Formula Ia, wherein R⁵═R⁶═H, andR¹⁴═R¹⁵═H, are the following compounds or pharmaceutically acceptablesalts thereof or tautomers thereof, wherein any atom not designated asdeuterium is present at its natural isotopic abundance:

TABLE 3 Example of Compounds of Formula Ia Compound R¹═R² R³═R⁴ R⁷R⁸═R¹¹ R⁹═R¹⁰ 300 OCD₃ OH D D D 301 OCH₃ OH D D D 302 OCD₃ OH D H D 303OCD₃ OH H D H 304 OCH₃ OH D H D 306 OCD₃ OH H H H 307 OCD₃ OH H D D 308OCH₃ OH H D D 309 OCD₃ OH H H D 310 OCH₃ OH H H D

In one embodiment, the compound is compound 300, 301, 302, 303, 304,306, 307, 308, 309 or 310 in Table 3, or a pharmaceutically acceptablesalt thereof or a tautomer thereof.

With reference to the geometry of the enolic double bond in thecompounds of Formula I and Ia, that is, the double bond shown as

the structures in each case have (E) stereochemistry or (Z)stereochemistry, or exist as a mixture of the two stereoisomers. Theabove stereoisomers or mixtures thereof are all encompassed by theinvention.

The invention encompasses tautomers of the compounds of Formula I andIa. With reference to the compound of Formula I, examples of tautomersinclude I-1 and I-2, shown below:

With reference to the compound of Formula Ia, examples of tautomersinclude Ia-1 and Ia-2, shown below:

With reference to the geometry of the enolic double bond in Formula I-2and Ia-2, that is, the double bond shown as

the structures in each case have (E) stereochemistry or (Z)stereochemistry, or exist as a mixture of the two stereoisomers. Theabove stereoisomers or mixtures thereof are all encompassed by theinvention.

Structures I-1 and Ia-1 at the carbon bonded to R⁷ have (R)stereochemistry or (5) stereochemistry, or exist as a mixture of the twostereoisomers. The above stereoisomers or mixtures thereof are allencompassed by the invention.

The synthesis of compounds of Formula I and Formula Ia may be readilyachieved by synthetic chemists of ordinary skill by reference to theExemplary Synthesis and Examples disclosed herein. Relevant proceduresanalogous to those of use for the preparation of compounds of Formula Iand Formula Ia and intermediates thereof are disclosed, for instance inLee, K H et al, Bioorg Med Chem, 2006, 14: 2527; Lee, K H et al, J MedChem, 2006, 49: 3963; Threadgill, M D et al, J Label Comp Radiopharm,2000, 43: 883; and Lee, K H et al, WO 03/088927 A2.

Such methods can be carried out utilizing corresponding deuterated andoptionally, other isotope-containing reagents and/or intermediates tosynthesize the compounds delineated herein, or invoking standardsynthetic protocols known in the art for introducing isotopic atoms to achemical structure.

Exemplary Synthesis

Compounds of Formula I and Formula Ia can be prepared by a personskilled in the art using appropriately deuterated reagents and/orintermediates according to the general procedures shown in Schemes 1-3.

A convenient method for synthesizing compounds of Formula Ia, whereinR¹═R², R³═R⁴, R⁵═R⁶ and R⁸═R¹¹ is depicted in Scheme 1(a). Treatment ofthe appropriately deuterated 3,4-dialkoxybenzaldehyde 10 (2 equivalents)with an appropriately deuterated 2,4-pentandione 11 having R⁹═R¹⁰ in thepresence of boric anhydride, tributyl borate, and n-butylamine underthermal conditions in a manner analogous to that described by Lee, K. H.et al., Bioorganic and Medicinal Chemistry, 2006, 14: 2527-2534 affordscompounds of Formula Ia.

Treatment of the appropriately deuterated starting material 12 withexcess 11 (wherein) R⁹═R¹⁰ as described above in Scheme 1(a) and in amanner analogous to that described by Lee, K H et al, J Med Chem, 2006,49: 3963, affords intermediate 13 which upon treatment with oneequivalent of a different appropriately deuterated 12′, affordscompounds of Formula I wherein R⁹═R¹⁰. As an example in Scheme 1b), X¹and X² are each independently CH or CD and R⁵ and R⁶ are eachindependently hydrogen or deuterium.

Conversely, 2 equivalents of starting material 12 may be treated with 1equivalent of an appropriately deuterated intermediate 11 as describedin Scheme 1(a) having R⁹ the same as R¹⁰or different from R¹⁰ to yieldcompounds of Formula I wherein R¹═R², R³═R⁴, R⁵═R⁶, R⁸═R¹¹ and X¹═X².

A method for the synthesis of appropriately deuterated3,4-dialkoxybenzaldehyde derivatives 10a-10d is shown in Scheme 2.Treatment of commercially available 3,4-dihydroxybenzaldehyde (8) orvanillin (9) with commercially available iodomethane-d3 in the presenceof potassium carbonate in a manner analogous to that described by Chem,J. W. et al., Journal of Organic Chemistry, 2002, 67: 6772-6787 affords3,4-bis(trideuteromethoxy)benzaldehyde (10a) or3-methoxy-4-(trideuteromethoxy)benzaldehyde (10c), respectively.Oxidation of deuterated benzaldehydes 10a and 10c with(diacetoxyiodo)benzene in methanol using a procedure analogous to thatdescribed by Karade, N. N. et al., Journal of Chemical Research, 2005:274-276 gives the corresponding deuterated methyl-benzoates. Reductionof the respective deuterated methyl-benzoates with lithium aluminumdeuteride followed by subsequent oxidation of the corresponding benzylicalcohols with pyridinium chlorochromate (PCC) using a procedureanalogous to that described by Luzzio, F. A. et al., Journal of OrganicChemistry, 1989, 54: 5387-5390 affords benzaldehydes 10b and 10d,respectively. Likewise, intermediates 12 and 12′, wherein X¹ and X² areeach independently CH, CD, C(OCH₃), C(OCD₃) or C(NO₂), may be preparedas described above starting with the appropriately substituted3,4-dihydroxybenzaldehyde in place of starting compound 8. Theseintermediates are of use for the preparation of compounds of Formula Ias outlined in Scheme 1b.

One approach to the synthesis of deuterated 2,4-pentandione 11b is shownin Scheme 3a, Commercially available 2,4-pentandione (11a) is treatedwith deuterated water in the presence of potassium carbonate underconditions of reflux according to the procedure described by Elguero, J.et al., Journal of Labelled Compounds and Radiopharmaceuticals, 1990,28: 967-970 to give the desired perdeuterated 2,4-pentanedione 11b.Treatment of 11b with water under conditions of reflux would allow theproton deuterium exchange at the 3-position to yield intermediate 11c.

Intermediate 11d may be prepared as shown in Scheme 3b and as describedby Ito, Y. et al., Bulletin of the Chemical Society of Japan, 1981,54(1): 150-8. Commercially available 2,4-pentandione (11a) stirred underreflux in the presence of deuterium oxide affords 3-d₂-2,4-pentandione(11d).

Intermediate 11f may be prepared as shown in Scheme 3c and as describedby Challacombe, K. et al., Journal of the Chemical Society, PerkinTransactions 1: Organic and Bio-Organic Chemistry (1972-1999); 1988,(8): 2213-18. Treatment of commercially available acetone-d₆ withlithium diisopropylamide followed by acetic anhydride affordsintermediate 11e which when treated with NaOH followed by affords1-d₃-2,4-pentandione (110.

The specific approaches and compounds shown above are not intended to belimiting. The chemical structures in the schemes herein depict variablesthat are hereby defined commensurately with chemical group definitions(moieties, atoms, etc.) of the corresponding position in the compoundformulae herein, whether identified by the same variable name (i.e., R¹,R², R³, etc.) or not. The suitability of a chemical group in a compoundstructure for use in the synthesis of another compound is within theknowledge of one of ordinary skill in the art.

Additional methods of synthesizing compounds of Formula I or Ia andtheir synthetic precursors, including those within routes not explicitlyshown in schemes herein, are within the means of chemists of ordinaryskill in the art. Synthetic chemistry transformations and protectinggroup methodologies (protection and deprotection) useful in synthesizingthe applicable compounds are known in the art and include, for example,those described in Larock R, Comprehensive Organic Transformations, VCHPublishers (1989); Greene, T W et al., Protective Groups in OrganicSynthesis, 3^(rd) Ed., John Wiley and Sons (1999); Fieser, L et al.,Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons(1994); and Paquette, L, ed., Encyclopedia of Reagents for OrganicSynthesis, John Wiley and Sons (1995) and subsequent editions thereof.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds.

Compositions

The invention also provides pyrogen-free pharmaceutical compositionscomprising an effective amount of a compound of Formula I (including anyof the formulae herein), or a pharmaceutically acceptable salt thereofor a tautomer thereof; and a pharmaceutically acceptable carrier. Thecarrier(s) are “acceptable” in the sense of being compatible with theother ingredients of the formulation and, in the case of apharmaceutically acceptable carrier, not deleterious to the recipientthereof in an amount used in the medicament.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

If required, the solubility and bioavailability of the compounds of thepresent invention in pharmaceutical compositions may be enhanced bymethods well-known in the art. One method includes the use of lipidexcipients in the formulation. See “Oral Lipid-Based Formulations:Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs andthe Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare,2007; and “Role of Lipid Excipients in Modifying Oral and ParenteralDrug Delivery: Basic Principles and Biological Examples,” Kishor M.Wasan, ed. Wiley-Interscience, 2006.

Another known method of enhancing bioavailability is the use of anamorphous form of a compound of this invention optionally formulatedwith a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), orblock copolymers of ethylene oxide and propylene oxide. See U.S. Pat.No. 7,014,866; and United States patent publications 20060094744 and20060079502.

The pharmaceutical compositions of the invention include those suitablefor oral, rectal, nasal, topical (including buccal and sublingual),vaginal or parenteral (including subcutaneous, intramuscular,intravenous and intradermal) administration. In certain embodiments, thecompound of the formulae herein is administered transdermally (e.g.,using a transdermal patch or iontophoretic techniques). Otherformulations may conveniently be presented in unit dosage form, e.g.,tablets, sustained release capsules, and in liposomes, and may beprepared by any methods well known in the art of pharmacy. See, forexample, Remington: The Science and Practice of Pharmacy, LippincottWilliams & Wilkins, Baltimore, Md. (20th ed. 2000).

Such preparative methods include the step of bringing into associationwith the molecule to be administered ingredients such as the carrierthat constitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers, liposomes orfinely divided solid carriers, or both, and then, if necessary, shapingthe product.

In certain embodiments, the compound is administered orally.Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, sachets, or tabletseach containing a predetermined amount of the active ingredient; apowder or granules; a solution or a suspension in an aqueous liquid or anon-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oilliquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatincapsules can be useful for containing such suspensions, which maybeneficially increase the rate of compound absorption.

In the case of tablets for oral use, carriers that are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried cornstarch. When aqueoussuspensions are administered orally, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring and/or coloring agents may be added.

Compositions suitable for oral administration include lozengescomprising the ingredients in a flavored basis, usually sucrose andacacia or tragacanth; and pastilles comprising the active ingredient inan inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example, sealed ampules and vials, and may be stored ina freeze dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tablets.

Such injection solutions may be in the form, for example, of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to techniques known in the art using suitabledispersing or wetting agents (such as, for example, Tween 80) andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions of this invention may be administered inthe form of suppositories for rectal administration. These compositionscan be prepared by mixing a compound of this invention with a suitablenon-irritating excipient which is solid at room temperature but liquidat the rectal temperature and therefore will melt in the rectum torelease the active components. Such materials include cocoa butter,beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art. See, e.g.: Rabinowitz J D and Zaffaroni A C, U.S. Pat. No.6,803,031, assigned to Alexza Molecular Delivery Corporation.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For topicalapplication topically to the skin, the pharmaceutical composition shouldbe formulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include mineral oil, liquidpetroleum, white petroleum, propylene glycol, polyoxyethylenepolyoxypropylene compound, emulsifying wax, and water. Alternatively,the pharmaceutical composition can be formulated with a suitable lotionor cream containing the active compound suspended or dissolved in acarrier. Suitable carriers include mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol, and water. The pharmaceutical compositions of thisinvention may also be topically applied to the lower intestinal tract byrectal suppository formulation or in a suitable enema formulation.Topically-transdermal patches and iontophoretic administration are alsoincluded in this invention.

Application of the subject therapeutics may be local, so as to beadministered at the site of interest. Various techniques can be used forproviding the subject compositions at the site of interest, such asinjection, use of catheters, trocars, projectiles, pluronic gel, stents,sustained drug release polymers or other device which provides forinternal access.

Thus, according to yet another embodiment, the compounds of thisinvention may be incorporated into compositions for coating animplantable medical device, such as prostheses, artificial valves,vascular grafts, stents, or catheters. Suitable coatings and the generalpreparation of coated implantable devices are known in the art and areexemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. Thecoatings are typically biocompatible polymeric materials such as ahydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethyleneglycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.The coatings may optionally be further covered by a suitable topcoat offluorosilicone, polysaccharides, polyethylene glycol, phospholipids orcombinations thereof to impart controlled release characteristics in thecomposition. Coatings for invasive devices are to be included within thedefinition of pharmaceutically acceptable carrier, adjuvant or vehicle,as those terms are used herein.

According to another embodiment, the invention provides a method ofcoating an implantable medical device comprising the step of contactingsaid device with the coating composition described above. It will beobvious to those skilled in the art that the coating of the device willoccur prior to implantation into a mammal.

According to another embodiment, the invention provides a method ofimpregnating an implantable drug release device comprising the step ofcontacting said drug release device with a compound or composition ofthis invention. Implantable drug release devices include biodegradablepolymer capsules or bullets, non-degradable, diffusible polymer capsulesand biodegradable polymer wafers.

According to another embodiment, the invention provides an implantablemedical device coated with a compound or a composition comprising acompound of this invention, such that said compound is therapeuticallyactive.

According to another embodiment, the invention provides an implantabledrug release device impregnated with or containing a compound or acomposition comprising a compound of this invention, such that saidcompound is released from said device and is therapeutically active.

Where an organ or tissue is accessible because of removal from thesubject, such organ or tissue may be bathed in a medium containing acomposition of this invention, a composition of this invention may bepainted onto the organ, or a composition of this invention may beapplied in any other convenient way.

In another embodiment, a composition of this invention further comprisesa second therapeutic agent. The second therapeutic agent may be selectedfrom any compound or therapeutic agent known to have or thatdemonstrates advantageous properties when administered with a compoundhaving the same mechanism of action as curcumin or dimethylcurcumin.Such agents include other androgen receptor antagonists.

Preferably, the second therapeutic agent is an agent useful in thetreatment of a disease or condition selected from baldness, hirsutism,behavioral disorders, acne, alopecia, skin lesions, Kennedy's disease orspinobulbar muscular atrophy and spermatogenesis where inhibition ofspermatogenesis is desired, psoriasis, Alzheimer's disease, mildcognitive impairment, asthma, type 2 diabetes, optic neuropathy,rheumatoid arthritis, osteoarthritis, major depressive disorder, kidneyallografts, oral lichen planus, irritable bowel syndrome (IBS),ulcerative colitis, Crohn's disease, chemoradiation side effectsincluding but not limited to radiation induced dermatitis andchemotherapy induced mucositis and cancer including, but not limited to,multiple myeloma, pancreatic cancer, myleodysplastic syndromes, coloncancer, colorectal cancer, skin cancer, small cell lung cancer,testicular cancer, lymphoma, leukemia, esophageal cancer, stomachcancer, breast cancer, endometrial cancer, ovarian cancer, centralnervous system cancer, liver cancer, prostate cancer, familialadenomatous polyposis (FAP), uterine cervical dysplasia, cutaneousT-cell lymphoma, head and neck cancer and osteosarcoma.

In another embodiment, the invention provides separate dosage forms of acompound of this invention and one or more of any of the above-describedsecond therapeutic agents, wherein the compound and second therapeuticagent are associated with one another. The term “associated with oneanother” as used herein means that the separate dosage forms arepackaged together or otherwise attached to one another such that it isreadily apparent that the separate dosage forms are intended to be soldand administered together (within less than 24 hours of one another,consecutively or simultaneously).

In the pharmaceutical compositions of the invention, the compound of thepresent invention is present in an effective amount. As used herein, theterm “effective amount” refers to an amount which, when administered ina proper dosing regimen, is sufficient to treat the target disorder.

The interrelationship of dosages for animals and humans (based onmilligrams per meter squared of body surface) is described in Freireichet al., Cancer Chemother. Rep, 1966, 50: 219. Body surface area may beapproximately determined from height and weight of the subject. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970,537.

In one embodiment, an effective amount of a compound of this inventioncan range from 50 mg to 2,000 mg/dose with a dosing of one to threetimes per day.

Effective doses will also vary, as recognized by those skilled in theart, depending on the diseases treated, the severity of the disease, theroute of administration, the sex, age and general health condition ofthe subject, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents and the judgment ofthe treating physician. For example, guidance for selecting an effectivedose can be determined by reference to the prescribing information forniacin.

For pharmaceutical compositions that comprise a second therapeuticagent, an effective amount of the second therapeutic agent is betweenabout 20% and 100% of the dosage normally utilized in a monotherapyregime using just that agent. Preferably, an effective amount is betweenabout 70% and 100% of the normal monotherapeutic dose. The normalmonotherapeutic dosages of these second therapeutic agents are wellknown in the art. See, e.g., Wells et al., eds., PharmacotherapyHandbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDRPharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition,Tarascon Publishing, Loma Linda, Calif. (2000), each of which referencesare incorporated herein by reference in their entirety.

It is expected that some of the second therapeutic agents referencedabove will act synergistically with the compounds of this invention.When this occurs, it will allow the effective dosage of the secondtherapeutic agent and/or the compound of this invention to be reducedfrom that required in a monotherapy. This has the advantage ofminimizing toxic side effects of either the second therapeutic agent ofa compound of this invention, synergistic improvements in efficacy,improved ease of administration or use and/or reduced overall expense ofcompound preparation or formulation.

Methods of Treatment

In one embodiment, the invention provides a method of treating a diseasethat is beneficially treated by dimethylcurcumin or curcumin in asubject in need thereof, comprising the step of administering to thesubject an effective amount of a compound of Formula I or Ia or apharmaceutically acceptable salt thereof or a tautomer thereof, or acomposition of this invention. Such diseases are well known in the artand include—baldness, hirsutism, behavioral disorders, acne, alopecia,skin lesions, Kennedy's disease or spinobulbar muscular atrophy andspermatogenesis where inhibition of spermatogenesis is desired,psoriasis, Alzheimer's disease, mild cognitive impairment, asthma, type2 diabetes, optic neuropathy, rheumatoid arthritis, osteoarthritis,major depressive disorder, kidney allografts, oral lichen planus,irritable bowel syndrome (IBS), ulcerative colitis, Crohn's disease,chemoradiation side effects including but not limited to radiationinduced dermatitis and chemotherapy induced mucositis and cancerincluding, but not limited to, multiple myeloma, pancreatic cancer,myleodysplastic syndromes, colon cancer, colorectal cancer, skin cancer,small cell lung cancer, testicular cancer, lymphoma, leukemia,esophageal cancer, stomach cancer, breast cancer, endometrial cancer,ovarian cancer, central nervous system cancer, liver cancer, prostatecancer, familial adenomatous polyposis (FAP), uterine cervicaldysplasia, cutaneous T-cell lymphoma, head and neck cancer andosteosarcoma.

In one particular embodiment, the method of this invention is used totreat a disease or condition selected from acne, alopecia, skin lesionsand Kennedy's disease or spinobulbar muscular atrophy.

In one particular embodiment, the method of this invention is used totreat a disease or condition selected from multiple myeloma, pancreaticcancer, myleodysplastic syndromes, colon cancer, colorectal cancer, skincancer, small cell lung cancer, testicular cancer, lymphoma, leukemia,esophageal cancer, stomach cancer, breast cancer, endometrial cancer,ovarian cancer, central nervous system cancer, liver cancer, prostatecancer, familial adenomatous polyposis (FAP), uterine cervicaldysplasia, cutaneous T-cell lymphoma, head and neck cancer andosteosarcoma.

In one particular embodiment, the method of this invention is used totreat a condition selected from baldness, hirsutism, behavioraldisorders, spermatogenesis where inhibition of spermatogenesis isdesired, psoriasis, Alzheimer's disease, mild cognitive impairment,asthma, type 2 diabetes, optic neuropathy, rheumatoid arthritis,osteoarthritis, major depressive disorder, kidney allografts, orallichen planus, irritable bowel syndrome (IBS), ulcerative colitis,Crohn's disease, and chemoradiation side effects including but notlimited to radiation induced dermatitis and chemotherapy inducedmucositis.

Identifying a subject in need of such treatment can be in the judgmentof a subject or a health care professional and can be subjective (e.g.opinion) or objective (e.g. measurable by a test or diagnostic method).

In another embodiment, any of the above methods of treatment comprisesthe further step of co-administering to the subject in need thereof oneor more second therapeutic agents. The choice of second therapeuticagent may be made from any second therapeutic agent known to be usefulfor co-administration with dimethylcurcumin. The choice of secondtherapeutic agent is also dependent upon the particular disease orcondition to be treated. Examples of second therapeutic agents that maybe employed in the methods of this invention are those set forth abovefor use in combination compositions comprising a compound of thisinvention and a second therapeutic agent.

The term “co-administered” as used herein means that the secondtherapeutic agent may be administered together with a compound of thisinvention as part of a single dosage form (such as a composition of thisinvention comprising a compound of the invention and an secondtherapeutic agent as described above) or as separate, multiple dosageforms. Alternatively, the additional agent may be administered prior to,consecutively with, or following the administration of a compound ofthis invention. In such combination therapy treatment, both thecompounds of this invention and the second therapeutic agent(s) areadministered by conventional methods. The administration of acomposition of this invention, comprising both a compound of theinvention and a second therapeutic agent, to a subject does not precludethe separate administration of that same therapeutic agent, any othersecond therapeutic agent or any compound of this invention to saidsubject at another time during a course of treatment.

Effective amounts of these second therapeutic agents are well known tothose skilled in the art and guidance for dosing may be found in patentsand published patent applications referenced herein, as well as in Wellset al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange,Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000),and other medical texts. However, it is well within the skilledartisan's purview to determine the second therapeutic agent's optimaleffective-amount range.

In one embodiment of the invention, where a second therapeutic agent isadministered to a subject, the effective amount of the compound of thisinvention is less than its effective amount would be where the secondtherapeutic agent is not administered. In another embodiment, theeffective amount of the second therapeutic agent is less than itseffective amount would be where the compound of this invention is notadministered. In this way, undesired side effects associated with highdoses of either agent may be minimized. Other potential advantages(including without limitation improved dosing regimens and/or reduceddrug cost) will be apparent to those of skill in the art.

In yet another aspect, the invention provides the use of a compound ofFormula I or Ia alone or together with one or more of theabove-described second therapeutic agents in the manufacture of amedicament, either as a single composition or as separate dosage forms,for treatment or prevention in a subject of a disease, disorder orsymptom set forth above. Another aspect of the invention is a compoundof Formula I or Ia for use in the treatment or prevention in a subjectof a disease, disorder or symptom thereof delineated herein.

EXAMPLES Example 1 Synthesis of(1E,4Z,6E)-1,7-bis(3,4-bis(trideuteromethoxy)phenyl)-5-hydroxyhepta-1,4,6-trien-3-one(Compound 212)

Step 1. 3,4-bis(trideuteromethoxy)benzaldehyde (10a): To a suspension of3,4-dihydroxybenzaldehyde (8, 5.0 g, 36.2 mmol) in acetonitrile (120mL), was added potassium carbonate (15.0 g, 108.6 mmol). The mixture wasstirred vigorously at ambient temperature for 15 minutes. To thisreaction mixture was added iodomethane-d₃ (7.2 mL, 115.84 mmol; Aldrich,99.5 atom % D) and then the mixture was heated to 45° C. for a period of15 hours. The mixture was then cooled to ambient temperature, filteredthrough Celite®, and concentrated in vacuo. The crude residue wasdiluted with EtOAc (100 mL) and water (100 mL) and the resulting aqueouslayer was further extracted with EtOAc (3×20 mL). The combined organiclayers were washed with 10% aqueous Na₂CO₃ (2×20 mL), dried (MgSO₄),filtered, and concentrated in vacuo to afford aldehyde 10a (5.2 g, 83%).MS (M+H): 173.2.

Step 2.(1E,4Z,6E)-1,7-bis(3,4-bis(trideuteromethoxy)phenyl)-5-hydroxyhepta-1,4,6-trien-3-one(Compound 212): A solution of acetylacetone (11a, 0.29 mL, 2.86 mmol)and boric anhydride (0.14 g, 2.0 mmol) in EtOAc (3 mL) was stirred at40° C. for a period of 30 min. To this mixture was added tributylborate(1.6 mL, 5.80 mmol) and aldehyde 10a (1.0 g, 5.80 mmol) and the mixturewas stirred at 40° C. for a period of 30 min. To the stirred mixture at40° C. was added dropwise over 15 min a solution of n-butylamine (0.44mL, 4.4 mmol) in EtOAc (3 mL). The yellow solution was stirred for aperiod of 24 hours at 40° C. then diluted with 4N HCl (10 mL) at whichpoint the temperature was raised to 60° C. for 30 min. The mixture wasthen cooled to ambient temperature and diluted with water (15 mL) andEtOAc (15 mL). The mixture was then extracted with EtOAc (3×20 mL) andthe combined organic layers washed successively with water and brine.The resulting organic layer was dried (Na₂SO₄), filtered, andconcentrated in vacuo. The resulting residue was purified by columnchromatography (SiO₂, 30-50% EtOAc/heptane) to afford Compound 212 as ayellow solid (0.13 g, 16%). ¹H NMR (CDCl₃, 400 MHz): δ 7.60 (d, J=15.6Hz, 2H), 7.15 (dd, J=8.4, 2.0 Hz, 2H), 7.08 (d, J=1.6 Hz, 2H), 6.88 (d,J=8.4 Hz, 2H), 6.50 (d, J=15.6 Hz, 2H), 5.82 (s, 1H). MS (M+H): 409.3.

Example 2 Synthesis of(1E,4Z,6E)-5-hydroxy-1,7-bis(3-methoxy-4-(trideuteromethoxy)phenyl)hepta-1,4,6-trien-3-one(Compound 214)

Step 1. 3-methoxy-4-(trideuteromethoxy)benzaldehyde (10c): To asuspension of vanillin (9, 5.0 g, 32.9 mmol) in acetonitrile (110 mL),was added potassium carbonate (6.8 g, 49.3 mmol). The mixture wasstirred vigorously at ambient temperature for 15 minutes. To thisreaction mixture was added iodomethane-d₃ (3.3 mL, 52.6 mmol; Aldrich,99.5 atom % D) and then the mixture was heated to 45° C. for a period of15 hours. The mixture was then cooled to ambient temperature, filteredthrough Celite®, and concentrated in vacuo. The crude residue wasdiluted with EtOAc (100 mL) and water (100 mL) and the resulting aqueouslayer was further extracted with EtOAc (3×20 mL). The combined organiclayers were washed with 10% aqueous Na₂CO₃ (2×20 mL), dried (MgSO₄),filtered, and concentrated in vacuo to afford aldehyde 10c (5.0 g, 90%).MS (M+H): 170.2.

Step 2.(1E,4Z,6E)-5-hydroxy-1,7-bis(3-methoxy-4-(trideuteromethoxy)phenyl)hepta-1,4,6-trien-3-one(Compound 214): A solution of acetylacetone (11a, 0.29 mL, 2.86 mmol)and boric anhydride (0.14 g, 2.04 mmol) in EtOAc (3 mL) was stirred at40° C. for a period of 30 min. To this mixture was added tributylborate(1.6 mL, 5.91 mmol) and aldehyde 10c (1.0 g, 5.91 mmol) and the mixturewas stirred at 40° C. for a period of 30 min. To the stirred mixture at40° C. was added dropwise over 15 min a solution of n-butylamine (0.45mL, 4.49 mmol) in EtOAc (3 mL). The yellow solution was stirred for aperiod of 24 hours at 40° C. then diluted with 4N HCl (10 mL) at whichpoint the temperature was raised to 60° C. for 30 min. The mixture wasthen cooled to ambient temperature and diluted with water (15 mL) andEtOAc (15 mL) followed by filtration through Celite®. The filtrate wasextracted with EtOAc (3×20 mL) and the combined organic layers werewashed successively with water and brine. The resulting organic layerwas dried (Na₂SO₄), filtered, and concentrated in vacuo. The resultingresidue was purified by column chromatography (SiO₂, 30-50%EtOAc/heptane) to afford Compound 214 as a yellow solid (0.10 g, 12%).¹H NMR (CDCl₃, 400 MHz): δ 7.61 (d, J=16.0 Hz, 2H), 7.15 (dd, J=8.4, 2.0Hz, 2H), 7.08 (d, J=2.0 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 6.50 (d, J=15.6Hz, 2H), 5.82 (s, 1H), 3.94 (s, 6H). MS (M+H): 403.2.

Example 3 Synthesis of(1E,4Z,6E)-1,7-bis(3,4-bis(trideuteromethoxy)phenyl)-1,2,6,7-tetradeutero-5-hydroxyhepta-1,4,6-trien-3-one(Compound 215)

Step 1. Methyl 3,4-bis(trideuteromethoxy)benzoate (15): To a suspensionof commercially available methyl 3,4-dihydroxybenzoate (14, 2.0 g, 11.89mmol) in acetonitrile (50 mL), was added potassium carbonate (4.9 g,35.67 mmol). The mixture was stirred vigorously at ambient temperaturefor 15 minutes. To this reaction mixture was added iodomethane-d₃ (2.4mL, 38.06 mmol; Aldrich, 99.5 atom % D) and then the mixture was heatedto 45° C. for a period of 15 hours. The mixture was then cooled toambient temperature, filtered through Celite®, and concentrated invacuo. The crude residue was diluted with EtOAc (100 mL) and water (100mL) and the resulting aqueous layer was further extracted with EtOAc(3×20 mL). The combined organic layers were washed with 10% aqueousNa₂CO₃ (2×20 mL), dried (MgSO₄), filtered, and concentrated in vacuo toafford ester 15 (2.3 g, 97%). MS (M+H): 203.2.

Step 2. 3,4-bis(trideuteromethoxy)benzaldehyde-d₁ (10b): To a solutionof ester 15 (2.3 g, 11.49 mmol) in THF (25 mL) at 0° C., was addedlithium aluminum deuteride (0.53 g, 12.6 mmol; Cambridge Isotope Labs,98 atom % D) and the solution was warmed to ambient temperature over aperiod of 2 hours. To the stirred solution was then added, water (0.53mL), 15% aqueous NaOH (0.53 mL), and additional water (1.6 mL). Theresulting cake was filtered through Celite® and the cake washed withEtOAc (20 mL). The resulting filtrate was concentrated in vacuo toafford the corresponding benzylic alcohol which was used without furtherpurification in the next step.

To a solution of the above benzylic alcohol (2.0 g, 11.34 mmol) inCH₂Cl₂ (40 mL) at 0° C., was added pyridinium chlorochromate (4.1 g,19.29 mmol) and the solution was warmed to ambient temperature over aperiod of 2 hours. To the stirred solution was then added heptanes (40mL) and Celite®. The resulting mixture was stirred at ambienttemperature for a period of 1 hour then filtered through a pad of SiO₂which was washed with CH₂Cl₂. The filtrate was concentrated in vacuo toafford aldehyde 10b (1.4 g, 71%). MS (M+H): 174.3.

Step 3.(1E,4Z,6E)-1,7-bis(3,4-bis(trideuteromethoxy)phenyl)-1,2,6,7-tetradeutero-5-hydroxyhepta-1,4,6-trien-3-one(Compound 215): A suspension of d₈-acetylacetone (11b, 0.43 g, 4.02mmol, prepared according to the procedure described by Doyle, G. et al.,Inorg. Chem. 1968, 7, 2479-2484), and boric anhydride (0.20 g, 2.78mmol) in EtOAc-d₃ (8 mL) was stirred at 40° C. for a period of 30 min.To this mixture was added tributylborate (2.2 mL, 8.06 mmol) andaldehyde 10b (1.4 g, 8.06 mmol) and the mixture was stirred at 40° C.for a period of 30 min. To the stirred mixture at 40° C. was addeddropwise over 15 min a solution of n-butylamine-N,N-d₂ (0.62 mL, 6.11mmol) in EtOAc-d₃ (5 mL). The yellow solution was stirred for a periodof 24 hours at 40° C. then diluted with 4N HCl (15 mL) at which pointthe temperature was raised to 60° C. for 30 min. The mixture was thencooled to ambient temperature and diluted with D₂O (10 mL) and EtOAc (20mL) followed by filtration through Celite®. The filtrate was extractedwith EtOAc (3×20 mL) and the combined organic layers were washedsuccessively with water and brine. The resulting organic layer was dried(Na₂SO₄), filtered, and concentrated in vacuo. The resulting residue waspurified by column chromatography (SiO₂, 30-50% EtOAc/heptane) to affordCompound 215 as a yellow solid (0.17 g, 15%). ¹H NMR (CDCl₃, 400 MHz): δ7.14 (dd, J=8.4, 2.0 Hz, 2H), 7.07 (d, J=2.0 Hz, 2H), 6.88 (d, J=8.4 Hz,2H), 5.82 (s, 1H); MS (M+H): 413.4.

Example 4 Synthesis of(1E,4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-(trideuteromethoxy)phenyl)hepta-1,4,6-trien-3-one(Compound 306)

(1E,4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-(trideuteromethoxy)phenyl)hepta-1,4,6-trien-3-one(Compound 306): A solution of acetylacetone (11a, 0.32 mL, 3.07 mmol)and boric anhydride (0.15 g, 2.19 mmol) in EtOAc (3 mL) was stirred at40° C. for a period of 30 min. To this mixture was added tributylborate(1.7 mL, 6.36 mmol) and commercially available 4-hydroxy-3-methoxy-d₃benzaldehyde (1.0 g, 6.36 mmol; Aldrich, 99 atom % D) and the mixturewas stirred at 40° C. for a period of 30 min. To the stirred mixture at40° C. was added dropwise over 15 min a solution of n-butylamine (0.48mL, 4.82 mmol) in EtOAc (3 mL). The yellow solution was stirred for aperiod of 24 hours at 40° C. then diluted with 4N HCl (12 mL) at whichpoint the temperature was raised to 60° C. for 30 min. The mixture wasthen cooled to ambient temperature and diluted with water (15 mL) andEtOAc (15 mL) followed by filtration through Celite®. The filtrate wasextracted with EtOAc (3×20 mL) and the combined organic layers werewashed successively with water and brine. The resulting organic layerwas dried (Na₂SO₄), filtered, and concentrated in vacuo. The resultingresidue was purified by column chromatography (SiO₂, 5% MeOH/CHCl₃) toafford Compound 306 as a yellow solid (0.109 g, 14%). ¹H NMR (CDCl₃, 400MHz): δ 9.94 (s, 1H), 7.59 (d, J=16.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H),7.05 (s, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.48 (d, J=16.0 Hz, 2H), 5.86 (brs, 2H), 5.80 (s, 1H). MS (M+H): 373.1.

Example 5 Synthesis of(1E,4Z,6E)-1-(3,4-bis(trideuteromethoxy)phenyl)-5-hydroxy-7-(4-hydroxy-3-(trideuteromethoxy)phenyl)hepta-1,4,6-trien-3-one(Compound 105)

Step 1.(3Z,5E)-6-(3,4-bis(trichloromethoxy)phenyl)-4-hydroxyhexa-3,5-dien-2-one(Compound 105): A suspension of acetylacetone (11a, 1.8 mL, 17.42 mmol),and boric anhydride (0.28 g, 4.06 mmol) in EtOAc (8 mL) was stirred at70° C. for a period of 30 min To this mixture was added tributylborate(1.6 mL, 5.80 mmol) and aldehyde 10a (prepared as described in Example1; 11.0 g, 5.80 mmol) and the mixture was stirred at 70° C. for a periodof 30 min at which point the reaction temperature was increased to 85°C. To the stirred mixture at 85° C., was added dropwise over 15 min asolution of n-butylamine (0.58 mL, 5.80 mmol) in EtOAc (3 mL). Theyellow solution was then stirred at 100° C. for a period of 1 hour thencooled to 50° C. and diluted with 1N HCl (15 mL) at which point themixture was maintained at 50° C. for 30 min. The mixture was then cooledto ambient temperature and diluted with water (20 mL) and EtOAc (20 mL)followed by filtration through Celite®. The filtrate was extracted withEtOAc (3×20 mL) and the combined organic layers were washed successivelywith water and brine. The resulting organic layer was dried (Na₂SO₄),filtered and concentrated in vacuo. The resulting residue was purifiedby column chromatography (SiO₂, 10-20% EtOAc/heptane) to afford diene 17(0.33 g, 22%). MS (M+H): 255.2.

Step 2.(1E,4Z,6E)-1-(3,4-bis(trideuteromethoxy)phenyl)-5-hydroxy-7-(4-hydroxy-3-(trideuteromethoxy)phenyl)hepta-1,4,6-trien-3-one(Compound 105): A suspension of diene 17, (0.33 g, 1.30 mmol), and boricanhydride (63 mg, 0.91 mmol) in EtOAc (3 mL) was stirred at 70° C. for aperiod of 30 min. To this mixture was added tributylborate (0.70 mL, 2.6mmol) and commercially available d₃-vanillin (16, 0.20 g, 1.30 mmol) andthe mixture was stirred at 70° C. for a period of 30 min at which pointthe reaction temperature was increased to 85° C. To the stirred mixtureat 85° C. was added dropwise over 15 min a solution of piperidine (0.13mL, 1.30 mmol) in EtOAc (2 mL). The yellow solution was then stirred at100° C. for a period of 1 hour then cooled to 60° C. and diluted with 1NHCl (15 mL) at which point the mixture was maintained at 60° C. for 30min. The mixture was then cooled to ambient temperature and diluted withwater (20 mL) and EtOAc (20 mL) followed by filtration through Celite®.The filtrate was extracted with EtOAc (3×20 mL) and the combined organiclayers were washed successively with water and brine. The resultingorganic layer was dried (Na₂SO₄), filtered, and concentrated in vacuo.The resulting residue was purified by column chromatography (SiO₂,30-50% EtOAc/heptane) to afford Compound 105 as a yellow solid (0.10 g,20%). ¹H NMR (CDCl₃, 400 MHz): δ 16.05 (br s, 1H), 7.60 (dd, J=16.0, 5.6Hz, 2H), 7.13 (dt, J=8.4, 2.0 Hz, 2H), 7.06 (dd, J=11.6, 1.6 Hz, 2H),6.90 (dd, J=23.2, 8.4 Hz, 2H), 6.49 (dd, J=15.6, 6.0 Hz, 2H), 5.81 (s,1H). MS (M+H): 392.2.

Example 6 Synthesis of(1E,4Z,6E)-1,2,6,7-tetradeutero-5-hydroxy-1,7-bis(4-hydroxy-3-(trideuteromethoxy)phenyl)hepta-1,4,6-trien-3-one(Compound 307)

(1E,4Z,6E)-1,2,6,7-tetradeutero-5-hydroxy-1,7-bis(4-hydroxy-3-(trideuteromethoxy)phenyl)hepta-1,4,6-trien-3-one(Compound 307): A suspension of 11b (0.19 g, 1.76 mmol, preparedaccording to the procedure described by Doyle, G. et al., Inorg. Chem.1968, 7, 2479-2484), boric anhydride (0.12 g, 1.76 mmol), andtributylborate (0.95 mL, 3.52 mmol) in DMF (2 mL) was stirred at 65° C.for a period of 15 min. To this reaction mixture was added d₄-vanillin(18, 0.55 g, 3.52 mmol) and the mixture was stirred at 65° C. for aperiod of 10 min. To the stirred mixture at 65° C., was added a solutionof 1,2,3,4-tetrahydroquinoline (0.05 mL) and AcOD (0.11 mL) in DMF (1mL). The yellow solution was then heated to 95° C. for a period of 4hours then cooled to ambient temperature and diluted with 20% AcOD/D₂O(10 mL) at which point the temperature was raised to 70° C. for 1 hour.The mixture was then cooled to ambient temperature and concentrated invacuo. The crude residue was diluted with EtOAc (100 mL) and water (100mL) and the resulting aqueous layer was further extracted with EtOAc(3×20 mL). The combined organic layers were dried (Na₂SO₄), filtered,and concentrated in vacuo. The resulting residue was purified by columnchromatography (SiO₂, 30-50% EtOAc/heptane) to afford Compound 307 as ayellow solid (0.26 g, 39%). ¹H NMR (CDCl₃, 400 MHz) δ 16.0 (br s, 1H),7.12 (dd, J=8.4, 2.0 Hz, 2H), 7.04 (d, J=1.6 Hz, 2H), 6.94 (d, J=8.0 Hz,2H), 5.86 (br s, 2H), 5.80 (s, 1H). MS (M+H): 379.1.

Example X Evaluation of Metabolic Stability

Microsomal Assay: Human liver microsomes (20 mg/mL) are obtained fromXenotech, LLC (Lenexa, Kans.). β-nicotinamide adenine dinucleotidephosphate, reduced form (NADPH), magnesium chloride (MgCl₂), anddimethyl sulfoxide (DMSO) are purchased from Sigma-Aldrich.

Determination of Metabolic Stability: 7.5 mM stock solutions of testcompounds are prepared in DMSO. The 7.5 mM stock solutions are dilutedto 12.5-50 μM in acetonitrile (ACN). The 20 mg/mL human liver microsomesare diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4,containing 3 mM MgCl₂. The diluted microsomes are added to wells of a96-well deep-well polypropylene plate in triplicate. A 10 μL aliquot ofthe 12.5-50 μM test compound is added to the microsomes and the mixtureis pre-warmed for 10 minutes. Reactions are initiated by addition ofpre-warmed NADPH solution. The final reaction volume is 0.5 mL andcontains 0.5 mg/mL human liver microsomes, 0.25-1.0 μM test compound,and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mMMgCl₂. The reaction mixtures are incubated at 37° C., and 50 μL aliquotsare removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well96-well plates which contain 50 μL of ice-cold ACN with internalstandard to stop the reactions. The plates are stored at 4° C. for 20minutes after which 100 μL of water is added to the wells of the platebefore centrifugation to pellet precipitated proteins. Supernatants aretransferred to another 96-well plate and analyzed for amounts of parentremaining by LC-MS/MS using an Applied Bio-systems API 4000 massspectrometer. The same procedure is followed for the non-deuteratedcounterpart of the compound of Formula I and the positive control,7-ethoxycoumarin (1 μM). Testing is done in triplicate.

Data analysis: The in vitro t_(1/2)s for test compounds are calculatedfrom the slopes of the linear regression of % parent remaining (In) vsincubation time relationship.

in vitro t_(1/2)=0.693/k

k=−[slope of linear regression of % parent remaining(ln) vs incubationtime]

Data analysis is performed using Microsoft Excel Software.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the illustrativeexamples, make and utilize the compounds of the present invention andpractice the claimed methods. It should be understood that the foregoingdiscussion and examples merely present a detailed description of certainpreferred embodiments. It will be apparent to those of ordinary skill inthe art that various modifications and equivalents can be made withoutdeparting from the spirit and scope of the invention.

We claim:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof or a tautomer thereof,wherein: R¹, R², R³ and R⁴ are each independently selected from thegroup consisting of —OH, —O(C₁-C₆ alkyl), —NO₂, —NH₂, —NH(C₁-C₆ alkyl)and —N(C₁-C₆ alkyl)₂, wherein each C₁-C₆ alkyl is optionally andindependently substituted with one or more deuterium; R⁵ and R⁶ are eachindependently hydrogen, deuterium, halo, or —NO₂; R⁷ is hydrogen,deuterium, or —R¹³; R¹³ is (C₂-C₆) alkenyl optionally substituted withone or more deuterium and substituted with —C(O)R¹²; R¹² is —OCH₃,—OCH₂CH₃, —NH(CH₂CH₃), —CN, or —CH₂OH, wherein each of —OCH₃, —OCH₂CH₃,—NH(CH₂CH₃), and —CH₂OH is optionally substituted with one or moredeuterium; R⁸ and R¹¹ are each independently hydrogen or deuterium; R⁹and R¹⁰ are each independently hydrogen or deuterium; X¹ and X² are eachindependently CH, CD, C(OCH₃), C(OCD₃) or C(NO₂); provided that at leastone of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹¹, R⁹, R¹⁰, X¹ and X² comprisesdeuterium; and provided that the compound of Formula I is not


2. The compound of claim 1, wherein R¹, R², R³, and R⁴ are independentlyselected from —OH, —OCH₃, and —OCD₃.
 3. The compound of claim 1, whereinR⁵ and R⁶ are each hydrogen or each deuterium.
 4. The compound of claim1, wherein R⁷ is hydrogen or deuterium.
 5. The compound of claim 1,wherein X¹ is CH or CD.
 6. The compound of claim 1, wherein X² is CH orCD.
 7. The compound of claim 1, wherein R⁷ is R¹³, wherein R¹³ is(C₂-C₆) alkenyl optionally substituted with one or more deuterium andwith —C(O)R¹², and R¹² is —OCD₃, —OCD₂CD₃, —N(H)CD₂CD₃, or —CD₂OH. 8.The compound of claim 1 wherein X¹═X²═CH, R⁵═R⁶═H and wherein thecompound is any one of the compounds of the following table, wherein anyatom not designated as deuterium is present at its natural isotopicabundance: Com- pound R¹ R² R³ R⁴ R⁷ R⁸ R⁹ R¹⁰ R¹¹ 100 OCD₃ OCD₃ OH OCD₃D D D D D 101 OCD₃ OCD₃ OH OCD₃ H D D D D 102 OCD₃ OCD₃ OH OCD₃ H H D DD 103 OCD₃ OCD₃ OH OCD₃ H D D D H 104 OCD₃ OCD₃ OH OCD₃ H H D D H 105OCD₃ OCD₃ OH OCD₃ H H H H H 106 OCD₃ OCD₃ OH OCD₃ H D H H D 107 OCD₃OCD₃ OH OCD₃ H D H H H 108 OCD₃ OCD₃ OH OCD₃ H H H H D 109 OCH₃ OCD₃ OHOCD₃ D D D D D 110 OCH₃ OCD₃ OH OCD₃ H D D D D 111 OCH₃ OCD₃ OH OCD₃ H HD D D 112 OCH₃ OCD₃ OH OCD₃ H D D D H 113 OCH₃ OCD₃ OH OCD₃ H H D D H114 OCH₃ OCD₃ OH OCD₃ H H H H H 115 OCH₃ OCD₃ OH OCD₃ H D H H D 116 OCH₃OCD₃ OH OCD₃ H D H H H 117 OCH₃ OCD₃ OH OCD₃ H H H H D 118 OCD₃ OCH₃ OHOCH₃ D D D D D 119 OCD₃ OCH₃ OH OCH₃ H D D D D 120 OCD₃ OCH₃ OH OCH₃ H HD D D 121 OCD₃ OCH₃ OH OCH₃ H D D D H 122 OCD₃ OCH₃ OH OCH₃ H H D D H123 OCD₃ OCH₃ OH OCH₃ H H H H H 124 OCD₃ OCH₃ OH OCH₃ H D H H D 125 OCD₃OCH₃ OH OCH₃ H D H H H 126 OCD₃ OCH₃ OH OCH₃ H H H H D 127 OCH₃ OCH₃ OHOCH₃ D D D D D 128 OCH₃ OCH₃ OH OCH₃ H D D D D 129 OCH₃ OCH₃ OH OCH₃ H HD D D 130 OCH₃ OCH₃ OH OCH₃ H D D D H 131 OCH₃ OCH₃ OH OCH₃ H H D D H132 OCH₃ OCH₃ OH OCH₃ H D H H D 133 OCH₃ OCH₃ OH OCH₃ H D H H H 134 OCH₃OCH₃ OH OCH₃ H H H H D

or a pharmaceutically acceptable salt thereof or a tautomer thereof. 9.The compound of claim 1, wherein the compound of Formula I is a compoundof Formula Ia:

or a pharmaceutically acceptable salt thereof or a tautomer thereof,wherein: R¹ and R² are the same and are selected from the groupconsisting of —OH, —O(C₁-C₆ alkyl), —NO₂, —NH₂, —NH(C₁-C₆ alkyl) and—N(C₁-C₆ alkyl)₂, wherein each C₁-C₆ alkyl is optionally andindependently substituted with one or more deuterium; R³ and R⁴ are thesame and are selected from the group consisting of —OH, —O(C₁-C₆ alkyl),—NO₂, —NH₂, —NH(C₁-C₆ alkyl) and —N(C₁-C₆ alkyl)₂, wherein each C₁-C₆alkyl is optionally and independently substituted with one or moredeuterium; R⁵ and R⁶ are the same and are selected from the groupconsisting of hydrogen and deuterium; R⁷ is selected from hydrogen anddeuterium; R⁹ and R¹⁰ are the same and are selected from hydrogen anddeuterium; R⁸ and R¹¹ are the same and are selected from hydrogen anddeuterium; R¹⁴ and R¹⁵ are the same and are selected from hydrogen anddeuterium; provided that at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R¹¹, R⁹, R¹⁰, R¹⁴ and R¹⁵ comprises deuterium; and provided that thecompound of Formula Ia is not


10. The compound of claim 9, wherein R¹ and R² are the same and areselected from —OH, —OCH₃ and —OCD₃; and R³ and R⁴ are the same and areselected from —OH, —OCH₃ and —OCD₃.
 11. The compound of claim 10,wherein R¹ and R² are the same and are selected from —OCH₃ and —OCD₃;and R³ and R⁴ are both —OH.
 12. The compound of claim 9, wherein R⁷, R⁹and R¹⁰ are the same and are selected from hydrogen and deuterium. 13.The compound of claim 1, wherein any atom not designated as deuterium ispresent at its natural isotopic abundance.
 14. The compound of claim 9,wherein R⁵═R⁶═H, and R¹⁴═R¹⁵═H, and wherein the compound is any one ofthe compounds of the following table, wherein any atom not designated asdeuterium is present at its natural isotopic abundance: Compound R¹═R²R³═R⁴ R⁷ R⁸═R¹¹ R⁹═R¹⁰ 200 OCD₃ OCD₃ D D D 201 OCD₃ OCH₃ D D D 202 OCH₃OCD₃ D D D 203 OCH₃ OCH₃ D D D 204 OCD₃ OCD₃ D H D 205 OCD₃ OCD₃ H D H206 OCD₃ OCH₃ D H D 207 OCD₃ OCH₃ H D H 208 OCH₃ OCD₃ D H D 209 OCH₃OCD₃ H D H 210 OCH₃ OCH₃ D H D 211 OCH₃ OCH₃ H D H 212 OCD₃ OCD₃ H H H213 OCD₃ OCH₃ H H H 214 OCH₃ OCD₃ H H H 215 OCD₃ OCD₃ H D D 216 OCD₃OCH₃ H D D 217 OCH₃ OCD₃ H D D 218 OCH₃ OCH₃ H D D 219 OCD₃ OCD₃ H H D220 OCD₃ OCH₃ H H D 221 OCH₃ OCD₃ H H D 222 OCH₃ OCH₃ H H D

or a pharmaceutically acceptable salt thereof or tautomer thereof. 15.The compound of claim 9, wherein R⁵═R⁶═H, and R¹⁴═R¹⁵═H, and wherein thecompound is any one of the compounds of the following table, wherein anyatom not designated as deuterium is present at its natural isotopicabundance: Compound R¹═R² R³═R⁴ R⁷ R⁸═R¹¹ R⁹═R¹⁰ 300 OCD₃ OH D D D 301OCH₃ OH D D D 302 OCD₃ OH D H D 303 OCD₃ OH H D H 304 OCH₃ OH D H D 306OCD₃ OH H H H 307 OCD₃ OH H D D 308 OCH₃ OH H D D 309 OCD₃ OH H H D 310OCH₃ OH H H D

or a pharmaceutically acceptable salt thereof or tautomer thereof.
 16. Apyrogen-free pharmaceutical composition comprising an effective amountof the compound of claim 1, or a pharmaceutically acceptable saltthereof or tautomer thereof; and a pharmaceutically acceptable carrier.17. A method of treating a disease selected from the group consisting ofbaldness, hirsutism, behavioral disorders, acne, alopecia, skin lesions,Kennedy's disease or spinobulbar muscular atrophy and spermatogenesiswhere inhibition of spermatogenesis is desired, psoriasis, Alzheimer'sdisease, mild cognitive impairment, asthma, type 2 diabetes, opticneuropathy, rheumatoid arthritis, osteoarthritis, major depressivedisorder, kidney allografts, oral lichen planus, irritable bowelsyndrome (IBS), ulcerative colitis, Crohn's disease, chemoradiation sideeffects, multiple myeloma, pancreatic cancer, myleodysplastic syndromes,colon cancer, colorectal cancer, skin cancer, small cell lung cancer,testicular cancer, lymphoma, leukemia, esophageal cancer, stomachcancer, breast cancer, endometrial cancer, ovarian cancer, centralnervous system cancer, liver cancer, prostate cancer, familialadenomatous polyposis (FAP), uterine cervical dysplasia, cutaneousT-cell lymphoma, head and neck cancer and osteosarcoma comprising thestep of administering to the subject an effective amount of a compoundof claim 1 or a pharmaceutically acceptable salt thereof or tautomerthereof.
 18. The method of claim 17 wherein the disease is selected frommultiple myeloma, pancreatic cancer, myleodysplastic syndromes, coloncancer, colorectal cancer, skin cancer, small cell lung cancer,testicular cancer, lymphoma, leukemia, esophageal cancer, stomachcancer, breast cancer, endometrial cancer, ovarian cancer, centralnervous system cancer, liver cancer, prostate cancer, familialadenomatous polyposis (FAP), uterine cervical dysplasia, cutaneousT-cell lymphoma, head and neck cancer and osteosarcoma.